Gene Regulatory Networks Computa.onal Genomics Seyoung Kim

Transcription

1 Gene Regulatory Networks Computa.onal Genomics Seyoung Kim

2 Transcrip6on Factor Binding

3 Transcrip6on Control Gene transcrip.on is influenced by Transcrip.on factor binding affinity for the regulatory regions of target genes Transcrip.on factor concentra.on Nucleosome posi.oning and chroma.n states Enhancer ac.vity

4 Gene Transcrip6onal Regulatory Network The expression of a gene is controlled by cis and trans regulatory elements Cis regulatory elements: DNA sequences in the regulatory region of the gene (e.g., TF binding sites) Trans regulatory elements: RNAs and proteins that interact with the cis regulatory elements

5 Gene Transcrip6onal Regulatory Network Consider the following regulatory rela.onships: Target gene1 TF Target gene2 Target gene3

6 Cis/Trans Regulatory Elements TF binding affinity can influence the target gene expression Target gene1 Target gene2 Target gene3 TF TF TF Binding site: cis regulatory element TF: trans regulatory element TF TF TF concentra6on can influence the target gene expression

7 Gene Transcrip6onal Regulatory Network Cis and trans regulatory elements form a complex transcrip.onal regulatory network Each trans regulatory element (proteins/rnas) can regulate mul.ple target genes Cis regulatory modules (CRMs) Mul.ple different regulators need to be recruited to ini.ate the transcrip.on of a gene The DNA binding sites of those regulators are clustered in the regulatory region of a gene and form a CRM

8 How Can We Learn Transcrip6onal Networks? Leverage allele specific expressions In diploid organisms, the transcript levels from the two copies of the genes may be different RNA- seq can capture allele- specific transcript levels

9 How Can We Learn Transcrip6onal Networks? Leverage allele specific gene expressions Teasing out cis/trans regulatory divergence between two species (WiZkopp et al. Nature 2004) First study that makes use of allele- specific gene expressions to learn about gene regulatory network Examines genome/transcriptome data for two parent species and their F1 progeny Allele- specific eqtl mapping Extension of eqtl mapping Examines popula.on genome/transcriptome data

10 Cis/trans regulatory Divergence in Two Species Compare two parent species with their F1 progeny

11 Only Cis- regulatory Divergence Between Two Species D. melanogaster TF Target Expr High High F1 Hybrid TF Target Expr High Low D. sechellia TF Target Expr Low Low

12 Only Trans- regulatory Divergence Between Two Species D. melanogaster TF Target Expr High High F1 Hybrid TF Target Expr Medium Medium D. sechellia TF Target Expr Low Low

13 Cis/Trans Regulatory Divergence and Allele- Specific Expression

14 More Precisely A, a: Two allele- specific transcript levels of target gene p, F1: parent species and F1 hybrid

15 More Precisely A, a: Two allele- specific transcript levels of target gene p, F1: parent species and F1 hybrid

16 How Much Cis/Trans Regulatory Divergence Between D. melanogaster and D. sechellia Only cis- regulatory divergence: genes on the diagonal line (y=x) Only trans- regulatory divergence: genes on y=1 Most genes are influenced by a combina.on of cis and trans regulatory divergence

17 How Much Cis/Trans Regulatory Divergence Between D. melanogaster and D. sechellia RNA- seq- based studies Cis + trans Allele specific ra.os have the same signs in parents and hybrids Cis/trans regulatory differences favored expression of the same allele during evolu.on Cis x trans Allele specific ra.os have different signs in parents and hybrids Cis/trans regulatory differences favored expression of the different allele during evolu.on Conserved no expression differences in the parents but differen.ally expressed in the hybrids. cis and trans divergence compensated with each other

18 Overall Regulatory Networks Regulatory genes Regulatory genes encode TFs, signaling molecules Expression changes lead to trans- ac.ng effects on downstream genes Structural genes Structural genes Encode enzymes or cellular components Usually terminal nodes with no trans- ac.ng effects

19 Limita6ons Examined the data between only two species and their progeny Limited sta.s.cal power Captured only the overall contribu.on of cis/trans regulatory divergence Unable to iden.fy the precise cis/trans regulatory elements whose varia.on contribute to the gene expression divergence

20 How Can We Learn Transcrip6onal Networks? Leverage allele specific gene expressions Teasing out cis/trans regulatory divergence between two species (WiZkopp et al. Nature 2004) First study that makes use of allele- specific gene expressions to learn about gene regulatory network Examines genome/transcriptome data for two parent species and their F1 progeny Allele- specific eqtl mapping (Sun, Biometrics 2012) Extension of eqtl mapping Examines popula.on genome/transcriptome data

21 Expression Quan6ta6ve Trait Locus (eqtl) Mapping Study of the gene.c basis of gene expression using popula.on gene expression and genotype data Essen.ally GWAS with gene expression as phenotype values eqtls for HLA- C gene expression in HapMap European samples

22 eqtl Mapping Popular approach for studying the gene.c basis of gene expressions for Different.ssue types Different diseases

23 Expression Quan6ta6ve Trait Locus (eqtl) Mapping Recombinant inbred lines, instead of popula.on of unrelated individuals Has been applied to model organisms yeast, mouse, etc.

24 Expression Quan6ta6ve Trait Locus (eqtl) Mapping Recombinant inbred lines, instead of popula.on of unrelated individuals Key ideas: shuffle their genomes through ma.ng, to understand the effects of gene.c differences in parent species. More genera.ons of ma.ng means more shuffling through recombina.ons and higher resolu.on for eqtls

25 Expression Quan6ta6ve Trait Locus (eqtl) Mapping Recombinant inbred lines, instead of popula.on of unrelated individuals At a given locus, the samples are separated according to the inherited alleles Expression of gene 1 Expression of gene 2

26 cis and trans eqtls cis eqtl: in genomes, the eqtl is located near the gene whose expression is affected by the eqtl. E.g., muta.ons in the upstream of a gene influences the expression level of the gene Cis eqtl TF X SNP promoter target gene 3 trans eqtl: in genomes, the eqtl is located far away (or on a different chromosome) from the gene whose expression is affected by the eqtl. E.g., muta.ons in the transcrip.on factor gene can influence the expression level of the TF target genes. Trans eqtl TF promoter TF gene TF X SNP promoter target gene 2

27 cis and trans eqtls Cis eqtls and its downstream effects, leading to trans eqtls

28 cis and trans eqtls In tradi.onal eqtl mapping, cis eqtls as local eqtls and trans eqtls as distant eqtls However, to be precise, not all cis eqtls are local and not all trans eqtls are distant (Rockman & Kruglyak, Nature Reviews Gene.cs 2006). Precisely, cis eqtls = cis regulatory varia.on Precisely, trans eqtls = trans regulatory varia.on

29 Not All Cis eqtls are Cis- regulatory Varia6on

30 Distant Regulatory Varia6on Affected gene expression Muta.on in the coding region of the regulator Pleiotropic effects of the regulatory varia.on Muta.on in the regulatory region of the regulator

31 Data for Allele- Specific eqtl Mapping Data prepara.on Gene expression data: Allele- specific expression data can be measured only if the exons for the transcript contain heterozygous loci Allele- specific expression can be measured only for individuals 1 and 2

32 Data for Allele- Specific eqtl Mapping Data prepara.on Genotype data: cis- regulatory effects can be assessed only if the allele- specific expression is measured AND the locus is heterozygous Cis- regulatory effects can be assessed only for individual 1 Haplotype informa.on btween SNPs and allele- specific transcript should be resolved

33 Allele- specific eqtls Cis eqtls = cis- regulatory varia.on Linear model with respect to the alleles Trans eqtls = trans- regulatory varia.on Linear model with respect to genotypes

34 Summary Cis/trans regulatory elements and the effects of their varia.on on gene expression How can we learn the underlying transcrip.onal network that consist of cis and trans regulatory elements? Cis/trans regulatory divergence can be assessed based on allele- specific expressions of two parent species and their F1 hybrid. However, this approach has limited power Cis/trans regulatory varia.on and their effects can be assessed in popula.on genome sequence and allele- specific expression data